Phenoxy-phenyl, phenylthiophenyl, phenylsulfonylphenyl and phenylaminophenyl diaminothioureas

ABSTRACT

New thio ureas in which a p-phenoxyphenyl, p-phenylthio-phenyl or p-phenylaminophenyl radical is attached to one nitrogen atom and which are substituted at the other nitrogen atom either by two lower alkyl groups or a polymethylene bridging member of 2 to 6 carbon atoms, whereby one of the methylene groups can be replaced by an optionally substituted imino group, processes for the production of the new compounds and compositions containing these compounds.

United States Patent [191 Spaun et al.

[ 1 PHENOXY-PHENYL,

PHENYLTHIOPHENYL, PHENYLSULFONYLPHENYL AND PHENYLAMINOPHENYL DLAMINOTHIOUREAS [75] Inventors: Rudiger Spaun, Bottmingen; Alain Claude Rochat, Birsfelden; Jean-Jacques Gallay, Magden; Paul Brenneisen, Basel, all of Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: Oct. 11, 1973 [21] Appl. No.: 405,619

Related US. Application Data [62] Division of Ser. No. 175,723, Aug. 27, 1971, Pat. No.

[30] Foreign Application Priority Data Dec. 23, 1975 3,803,198 4/1974 Durr 71/99 FOREIGN PATENTS OR APPLICATIONS 65,701 11/1969 Germany 71/99 92,938 3/1962 Denmark 71/99 OTHER PUBLICATIONS Iyengar et al., Chemical Abstracts, Vol. 47, col. 1633 (1953).

Primary Examiner-James 0. Thomas, Jr. Assistant Examiner-G. Breitenstein Attorney, Agent, or Firml-Iarry Falber; Frederick H.

Rabin 57 ABSTRACT New thio ureas in which a p-phenoxyphenyl, p-

phenylthio-phenyl or p-phenylaminophenyl radical is attached to one nitrogen atom and which are substituted at the other nitrogen atom either by two lower alkyl groups or ,a polymethylene bridging member of 2 to 6 carbon atoms, whereby one of the methylene groups can be replaced by an optionally substituted imino group, processes for the production of the new compounds and compositions containing these compounds. 1

4 Claims, No Drawings PHENOXY-PHENYL, PHENYLTHIOPHENYL, PHENYLSULFONYLPHENYL AND PHENYLAMINOPHENYL DIAMINOTHIOUREAS This is a division of application Ser. No. 175,723, filed on Aug. 27, I971 now US. Pat. No. 3,781,290.

The present invention relates to new thio ureas, a processfor the manufacture of these compounds and their use for combating parasitic Helminths.

According to the present invention there are provided thio ureas of general formula I:

in which R is hydrogen, halogen, hydroxyl, nitro, carboxyl, low alkyl, low alkoxy, alkoxycarbonyl, low alkylthio, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino or sulfamoyl, R is hydrogen, halogen, nitro or low alkyl, alkoxycarbonyl or carboxyl, R is hydrogen, halogen, nitro or carboxyl, and R and R are each low alkyl or together area polymethylene bridge having 2 to 6 carbon atoms, wherein one methylene group can be replaced by the group N-R in which R is hydrogen, low alkyl or hydroxyalkyl, phenyl or benzyl, and X is oxygen, sulphur, sulfonyl or imino (NH-).

In this formula, by low alkyl for R R R and R there are to be understood straight or branched-chain alkyl groups having I to 4 carbon atoms, e.g., methyl,

ethyl, n-propyl, isopropyl, or 'one of the four isomeric butyl groups. Such alkyl groups also form the alkyl part of R when that is alkoxy, alkylthio, alkylamino, dialkylamino, or alkoxy carbonyl. Low alkanoyl groups such as acetyl, propionyl, butyryl, valeryl, isobutyryl, are to be understood as acyl substitutes of an acyl amino group R 1 Any heterocyclic group formed by groups R, and R and the neighboring nitrogen atom preferably has 5-7 ring members. Such heterocycles are, for example, pyrrolidine, piperidine, hexahydroazepine, piperazine, N-methyl-piperazine and N-phenyl-piperazine. The group R by which the heterocycles with 2 nitrogen atoms can be substituted has thesame meanings when low alkyl as given above for R R R and R By halogen, fluorine, chlorine, bromine and iodine are to be understood, chlorine and bromine being preferred.

The new thio ureas of. formula I are manufactured according to the invention by reacting an iso-thiocyana te of formula II:

in which R R R and X have the meaning given under formula I with an amine of the formula III:

in which R and R are each low alkyl or form together with a polymethylene bridge having 3 to 6 carbon atoms, wherein one of the methylene groups can be replaced by the group NR in which R is a low alkyl group, hydroxyalkyl group, phenyl group, benzyl group, or a low alkoxycarbonyl group, and if desired transforming compounds obtained in which R, is a nitro group by reduction and compounds=in which R is an acylaminoor alkoxycarbonyl amino group and/or compounds in which R is an alkoxycarbonyl amino group by hydrolysis into compounds of formula I in which R is the amino group and/or R is hydrogen. The hydrolytic splitting off of lowalkoxy carbonyl groups or acyl groups takes place preferably in alkali medium, for example by warming the compound obtained in aqueous alkali metal hydroxide solution.

The reaction is advantageously carried out at room temperature or slightly elevated temperature in an inert solvent. As solvents are suitable, for example, aromatic hydrocarbons, for instance benzene, toluene, or aliphatic or aromatic halogenated hydrocarbons such as methylene chloride, chloroform, chlorobenzene, as well as ether and ether compounds such as diethyl ether and dioxane, as well as N-alkylated acid amides such as dimethyl formamide as well as mixtures of the solvents with one another, also water or mixtures of the solvents with water.

The isothiocyanates of the formula 11 used as starting materials can be obtained according to known methods, for example by reaction of amines of the general formula lV wherein R R R and X'have the meaning given under formula I, with thiophosgene. (c.f. Swiss Pat.'No. 470.846 and Belgian Pat. No. 736.010).

The new thio ureas of formula I can also be obtained by reacting a thiocarbamicacid-derivative of formula with an amine of formula III and if desired converting compounds obtained in'which R is a nitro group by reduction and compounds by which R is an acylamino or alkoxycarbonyl amino group and/or compounds in which R is an alkoxycarbonyl amino group by hydrolysis into compounds of formula I in which R is the amino group and/or R is hydrogen. The reaction is carried 'out advantageously at room temperature or slightly elevated temperature in. an inert solvent. Suitable inert solvents are, for example aromatic hydrocar bons, for instance benzene, toluene, or aliphatic or aromatic halogenated'hydrocarbons such as methylene chloride, chloroform, chlorobenzene, as well as ether and ether compounds, as well as N-alkylated acid amides such as dimethyl formamide as well as mixtures of the solvents withone another, also water or mixtures of the solvents with water.

The starting materials of the general formula V can be obtained by reacting an amine of the general formula IV with a halothiocarboxylic acid-O-phenylester in the presence of an acid binding agent. As acid binding agents there are preferably used tertiary amines such as trialkylamine, pyridine bases etc., also hydroxides and carbonates of alkali and alkaline earth metals.

A further process for the manufacture of the novel thio ureas of formula I consists in reacting an acylated amine of formula VI:

in which R is an acyl group easily removable by hydrolysis, with a thio carbamoyl halide of formula VII:

(VII) in which Hal is chlorine or bromine in the presence of an acid binding agent and alkaline hydrolysing the resulting thio urea to remove the acyl group R and if desired transforming compounds obtained in which R is a nitro group by reduction and compounds in which R is an acyl amino or alkoxycarbonyl amino group and/or compounds in which R is an alkoxy carbonyl amino group by hydrolysis into compounds of formula I in which R is the amino group and/or R is hydrogen. In formulae VI and VII the symbols R R R,, and R have the meanings given for formula I and formula II] respectively.

The reaction is advantageously performed at elevated temperature, preferably at reflux temperature of the reaction mixture, in an inert solvent. Suitable inert solvents are, for example, hydrocarbons, for instance benzene, toluene, or aliphatic or aromatic halogenated hydrocarbons such as methylene chloride, chloroform, chlorobenzene, as well as ether and ether compounds such as diethyl ether and dioxane, as well as N- alkylated acid amides such as dimethylformamide as well as mixtures of the solvents with one another, also water or mixtures of the solvents with water.

The starting materials of the formula VI are obtained according to known methods by alkylation of amines of the formula IV.

Suitable easily split off groups R by hydrolysis are the trifluoroacetyl group and the tertiarybutoxycarbonyl group. For the alkaline hydrolysis, preferably inorganic bases such as alkali metal hydroxides are used. As acid binding agent, particularly tertiary amines may be used, for example trialkylamine but also inorganic bases such as hydroxides and carbonates of alkali and alkaline earth metals may be used. Additionally, for this reaction amines of formula IV can be used which are acylated by a carbobenzoxy group, in those cases where R and R are not nitro. The carbobenzoxy group is then removed by hydrogenolysis with catalytic hydrogen.

The new thio ureas of formula I in which one of symbols R and R means a group which is able to form salts, e.g., an alkyl or a dialkyl amino group or the carboxyl group, can be transformed into the corresponding salts with acids or bases which are'nontoxic for human and animal organisms. As acids both inorganic and organic acids are of value, for example, hydrohalic acids, sulphuric acid, phosphoric acids, acetic acid, aminoacetic acid, butyric acid, lauric acid, stearic acid, oxalic acid, adipic acid, maleic acid, tartaric acid, lactic acid, methanesulphonic acid, p-toluenesulphonic acid, etc. As bases there should be noted particularly alkaline and alkaline earth metal hydroxides and alkanolates, as well as quaternary ammonium bases and ammonium salts.

For the manufacture of quaternary ammonium salts, the new thio ureas of formula I in which R is a dialkyl amino group can be transformed into the corresponding ammonium salts by conventional quaternisation agents such as alkyl halides, dialkyl sulphates, toluene sulphonic acid esters, etc. If the anion of the quaternary salt obtained is toxic for human and animals, then it can be exchanged by reaction with a non-toxic acid for a non-toxic anion.

The following examples will illustrate the manufacture of novel thioureas of formula I. The subsequent table shows further thio ureas which can be manufactured using the process of the example. Temperatures given are in C throughout.

EXAMPLE 1 A solution of 10 g 4-nitro-4-isothiocyano-diphenylamine in ml toluene was treated at a temperature of 50 with stirring with a solution of 6.3 ml dibutylamine in 20 ml toluene. After 3 hours stirring at 50 the solution was filtered from the precipitate obtained. By recrystallising the crude product from methanol 10.9 g N-[4-(4-nitroanilino)-phenyl]-N,N-dibutylthio urea of melting point 179l 83 were obtained.

EXAMPLE 2 A solution of4 g N-[4-phenoxyphenyl]-thiocarbamic acid-O-phenyl ester in 50 ml toluene was reacted at a temperature of 50 for 3 hours with 10 ml diethylamine (15% aqueous solution). After, separation of the aqueous phase the organic phase was washed with water, dried "over calcium chloride, filtered and evaporated away. The recrystallisation of the crude product from ethanol gave 2.4 g N-(4-phenoxyphenyl)-N',N-diethylthio urea of melting point 7879.

EXAMPLE 3 A solution of 4.9 g 4-nitro-4-trifluoroacetamidodiphenylether, 2.3 g N,N-diethylthiocarbamoyl chloride, and 2.1 ml triethylamine in ml toluene was boiled under reflux for 12 hours. The triethylamine hydrochloride formed was filtered off and the filtrate was evaporated to dryness in vacuo. For removal of the trifluoroacetyl group the crude product was dissolved in hot benzene and boiled under reflux in the presence of 1 g powdered KOH for 2 hours. The benzene solution was washed with water, dried over potash, filtered and evaporated off. The residue was recrystallised from ethanol. 1.8 g N-[4-(4'-nitrophenoxy)-phenyl]-N',N'- diethylthio urea was obtained of melting point l38-l40.

Further compounds obtained are shown in the following table:

-continued "C Compound Melting point pheny1]-NN'-dihexy1thio urea n 1,568 N-[4-(4'-Methylphenoxy)-pheny1]-NN'- dibutylthio urea n 1,5725 N-[4-(4'-Bromphenoxy)-phenyl]-N'N- dibutyllhio urea n 1,5925 N-[4-(4'-N,N-Dimethy1aminophenoxy)- pheny1]-N'N'-dibuty1thio urea n 1,6103 N-[4-(4'-Methy1phenoxy)-pheny1]NN'- dihexylthio urea n 1,5631 N-[4-(4'-Methoxyphenoxy)-pheny1]-N'- ethy1-N-sec.buty1thio urea 89-90 N-[-(4'-Nitro henoxy)-pheny1]-N'- ethy1-N-sec.- uty1th1o urea 104-05 N-[4-(4'-Acetaminophen0xy)-pheny1]- N'-ethy1-N'-sec.-buty1thio urea 158-60 N-[4-(4'-Aminophenoxy)-pheny1]-N'N- dibutylthio urea n 1,6082 N-[4-(4'-Methylphenoxy)-pheny11- N'-ethyl-N'-sec.-bulylthio urea n 1,6078 N-[4-(4'-Methylthiophenylthio)-phenyl] -N'N'-dimethy1thio urea l5657 N-[4-(4'-Methy1phenylthio)-phenyl]- N'N'-diethylthio urea 74-75 N-[4-(4'-Ch1o1'pheny1thio)-pheny1]- N'N'-dimethy1thio urea 163-64 N-[4-(4'-Acetaminophenylthio)-phenyl]- N'N'-diethy1thio urea 190-91 N-[4-(4'-Acetaminopheny1thio)-pheny1]- N'N'-dimethy1thio urea 198-99 N-[4-(4-Nitrophenylthio)-pheny1]- N'N'-diethy1thi0 urea 109-12 N-[4-(4'-Chl0rpheny1thio)-pheny1]- N'N-diethy1thi0 urea 70-71 N-[4-(4'-Ch101'phenylthio)-3-carboxyphenyl]-N'N'-dimethy1thio urea 80-82 Compound Making point (0) -continued Compound Melting point N-[4-(4'-Nitroanilino)-phenyl]- N'N'-dibutylthio urea 179-83 N-[4-(4'-N|troanilino)-phenyl- N'N'-dihexylthio urea 134-39 N-[4-(4'-Bromanilin0)-phenyl]-N'N'- dibut lthio urea 128-32 N[4- 4'-N,N-Dimethylaminoanilino)- phenyl]-N'N'-dibutylthio urea 98 N-[4-(4'-Methoxyanilino)-phenyl]- N'N-dibutylthio urea v 1 -20 N-[4-(4'-Methoxyanilino)-phenyl1- N N' -dimethylthio urea -95 N-[4-(4'-Chloranilino)-phenyl]- N'methy1-N'-pro ylthio urea -138 N-[4-(4'-Nitroani1ino)-'pheny|]- N methyl-N'-propylthio urea 159-161 N-[4-(4'-Hydroxyanilino)-phenyl]- N'.N'-diethylthio urea 72-76 N-[4-( 3',4'-Dimethylanilino)-phenyl]- N'-ethyl-N-sec-butylthio urea 95-100 N-[4'(4'-Methoxyanilino)-phenyl]- N'-ethyl-N-sec-butylthio urea 80-84 N-[4-(3'-Methoxyanilino)-phenyl]- N',N'-diethylthio urea 134-140 4-Methoxy-4'-( N-methylpiperazinyl thiocarbonylamino-diphenylether 138-140 4-Methyl-4'-(N-methylpiperazinyl)-thiocarbonylamino-diphenylether 134-137 4-Nitro-4'-(N-methylpiperazinyl)-thiocarbonylamino-diphenylether 168-169 4-Brom-4'-(N-methylpiperazinyl)-thiocarbonylamino-dipheny ether 151-152 4-Methylthio-4'-( N-methylpiperazinyl thiocarbonylamino-diphenylamine 164-166 4-Methyl-4'-(N-methylpiperazinyl)-thiocarbonylamino-diphenylamine -152 4-Chlor-4'-( N-methylpiperazinyl )-thiocarbonylamino-diphenylamine 165-167 4-Nitro-4'-(N-methylpiperazinyl)-thiocarbonylamino-diphenylamine 191-196 4-Chlor-3'-carboxy 4'-(N-methylpiperazinyl )-thiocarbonylamino-diphenylamine 188-190 4-nitro-4'-( N-phenylpiperazinyl )-thio carbonylamino-diphenylethe r 7 183-88 4-(n-methylpiperazinyl)-thiocarbonylamino-diphenylether 138-42 4-(n-phenylpiperazinyl)-thiocarbonylamino-di henylether -73 4- nitro-4 -(n-ethoxycarbonylpiperazinyl)- thiocarbonylamino-diphenylether 185-88 4-nitro-4'-( N-hydroxyethylpiperazinyl thiocarbonylamino-dlphenylether 165-67 4-( N-hydroxyethylpiperazinyl )-thiocarbonylamino-diphenylether v 137-40 2,4-dinitro-4-(N-methylpiperazinyl)- thiocarbonylamino-diphenylether 197-99 4-bromo-4 -(N-ethoxycarbonylpiperazinyl thiocarbonylamino-diphenylether 140-44 4-nitro-4'-(N-ethylgiperazinyl)-thiocarbonylamino-dip enylether 159-63 4-methoxy-4'-( N-ethylpiperazinyl )-thiocarbonylamino-diphenylether 138-40 4-nitro-4-( N-propylpiperazinyl )-thiocarbonylamino-diphenylether 149-50 4-nitro-4-(N-butyl iperazinyl)-thiol carbonylamino-dip' enylether 124-26 4(N-i-propylpiperazinyl)-thiocarbonylamino-di henylether I 130-33 4-nitro-4 -(N-i-pro ylpiFerazinyU-thiocarbonylamino-dip eny ether 155-58 4-nitro-4'-(N-phenylpiperazinyl)-thiocarbonylamino-di henylamine 235-40 4-meth lthio-4'-( henylpiperazinyl)- thiocar on laminoiphen lamine 175-80 4-nitro-4'- N-hydroxyethy piperazinyl)- thiocarbonylamino-di henylamine -200 2.4-dimetl1yl-4-(N-et ylpiperazinyl)- thiocarbonylamino-diphenylamine 167-71 The new thio ureas of formula I are suitable for comthe animals die from. It is thus of the greatest imporbatmg parasitic helminths and their stages of developtance to develop agents which on the one hand will ment. Among the endo-parasites which attack domesprophylactically hinder the attack by such endo-paratic and useful animals, parasitic helminths are particu- 65 sites, but which on the other hand will also have a good larly dangerous pests. Thus it is often the case with anthelmintic action with a broad spectrum of activity. attacked animals that there is both a retarded growth Previously known ureas and thio ureas with anthelminand disease is released by the helminth attack which tic action have not heretofore been satisfactory be- 1 1 cause in compatible doses they have insufficient action while in therapeutically active doses they show undesirable side effects or alternatively have too narrow a spectrum of activity.

Ureas such as 3,5-bis-trifluoromethyl-4-nitrodiphenyl urea and 3,5,3-tris-trifluoromethyldiphenyl urea (both compounds included in Belgian Pat. No. 616735, the first in the examples thereof) also show good activity but in the concentrations required to be used, show also a strong irritant activity, which leads to extremely thin liquid droppings in hens and diarrhoea in sheep and horses. Thus, for example, the thio ureas known from British patent specification No. 956520, the 3,3,5-tris-trifluoromethyldiphenylthio urea and the N-(3,5-bis-trifluoromethylphenyl)-N'-(3-chlorophenyl)-thio urea show no action at a concentration of a 100 mg per kg body weight against Ascaridia galli in hens and enterobius in mice, while giving substantial toxic side effects at 500 mg/kg body weight.

The thio ureas of formula I according to the invention are not toxic in normal use concentrations (compare the following tests). They are very compatible with domestic and useful animals and have a broad spectrum of activity. The new active substances are particularly suitable for combating parasitic nematodes (e.g., Ascaridae, Trichostrongylidae, Ancylostomatidae), cestodes (e.g., Taeniidae, Anoplocephalidae, Hymenolepidae) and trematodes (e.g., Fasciolidae) in domestic and useful animals such as cattle, sheep, goats, horses, pigs, cats, dogs and birds.

Of particular value on the basis of their good compatability and activity are thio ureas of formula la 4 R \C X 01m cs N/ in which R is halogen, particularly chlorine, nitroor a low alkyl group, X is oxygen, sulphur or the imino group (-NH) and R and R have the meaning given under formula I, particularly those in which R and R together with the nitrogen atom to which they are bonded, form an N-substituted piperazine group.

The new active agents can be used in the form of solutions, emulsions, suspensions, drenches, powders, tablets, boluses, and capsules and can be administered per orally or abomasally to the animals directly, either in a single dose or the dose can be repeated. In most cases, better effect is obtained by protracted administration but results can be obtained with smaller total doses. The active agent or mixtures containing it can also be added to the food or drink for the animals or it can be contained in so-called food premixes.

For preparing application forms, it is customary to use solid carrier materials for example, kaolin, talcum, bentonite, cooking salt, calcium phosphate, carbohydrates, cellulose powder, cotton seed meal, carbowaxes, gelatine, or liquids such as water, optionally with the addition of surface active agents such as ionic or non-ionic dispersing agents as well as oils or other solvents which are not harmful to the animal organisms. If the anthelmintic agent is to be in the form of a food concentrate, then as carrier materials there may be used for example, energy foods, crop foods or protein concentrates. Such food concentrates can contain apart from the active agent of this invention, other additives such as vitamins, anti-biotics, chemotherapeutic agents, bacteriostatic agents, fungistatic agents, coccidostatic agents, hormone preparations, materials with anabolic action or other materials which improve growth or influence the quality of the meat of the slaughtered animal or substances which are useful for the animal in other ways.

Suitable dose forms for oral administration such as dragees and tablets preferably contain 100 500 mg of the active substance according to the invention and indeed, 20-80% of a compound of the general formula I. For their manufacture the active substance may be combined, e.g., with solid powder carrier materials such as lactose, saccharose, sorbitol, mannitol, starches such as potato stach, maize starch or amylo pectin, or laminaria powder or citrus pulp powder, cellulose derivatives or gelatine, optionally with the addition of lubricants'such as magnesium or calcium stearate or polyethylene glycols, and formed to tablets or dragee cores. The latter is preferably coated for example with concentrated sugar solution which, for example, can contain gum arabic, talc and/or titanium dioxide, or they can be coated with a laquer dissolved in a highly volatile organic solvent or organic solvent mix. These coatings can also include dyes or pigments in order to be able to characterize various doses of active substance optically.

Determination of anthelmintic action in hens which were infested with Ascaridia galli 1-3 day old chicks were artificially infested with eggs of Ascaridia galli (helminths). Groups of five hens each were used per test. 45 weeks after infestation, the active substance was administered to the animals in 1 dose per day on 3 subsequent days. As control infested hens which were not medicated were used. Evaluation The number of Ascaridia galli excreted per test group over the course of 5 days after the first administration of the active substances was determined daily and the number still present in the gut on the 5th test day was also determined by section. Additionally, the number of worm-free hens was determined.

Results are shown in the following table.

No. of Ascaridia galli of 5 hens Active Substance Daily dose Excreted during No. of General mg/kg the period found worm-free Condition body weight of test on hens absolof total sectioute No. number ning 4-[4-(4'-Nitrophenoxy)-phenyl]NN'- 750 63 100 O 5 good diethylthio urea N-[4-(4-Nitrophenoxy)-phenyl]- N'N'-dipropylthio 750 47 100 0 5 good No. of Ascaridia galh of S hens Excreted during the period of test absolof total ute N0. number worm'free continued No. of General Condition hens urea N-[4-(4-Nitrophenoxy)-phenyll-N'N- dibutylthio urea N[4-(4-Chlor-3'- methyl henoxy)- phenyl -N'N'-diethylthio urea N[4-(4'Nitrophenoxy)- henyl]-N'N'- dihexy thio urea N-[4-(4'-Nitrophe noxy)-phenyl]-N'- methyl-N'-propylthio urea N-[4-(4-Chlorphenoxy)-phenyl]-N'N'- dibutylthio urea N[4-(4"-Methoxyphenoxy)-phenyl]- N'ethyl-N -sec butylthio urea N-[4-(4'-Nitrophenoxy)-phenyl]-N'- ethyl-N"sec.butylthio urea N-[4-(4-Bromanilino)-phenyl]-N'- N'-diethylthio urea N-[4-(34'-Dimethylanilino)-phenyl]-N diethylthio urea N-[4-(4-Methoxyanilino)-3-carboxyphenyl NN'-diethylthio urea N-[4-(4-Nitroanilino)- phenyl]-N'N'-dihexylthio urea N-[4-(3'4'-Dimethylanilino) -phenyl]-N' ethyl- N'-sec.butylthio urea 4-Methoxy-4'-(N-methylpiperazinyl)-thiocarbonylamino-diphenylether 4-Nitro-4'-(N-methylpiperazinyl)-thiocarbonylamino-diphenylether 4Methylthio-4'-(N-methylpiperazinyl )-thiocarbonylamino-diphenylamine 4-ethyl-4'-( N-methylpiperazmyU-thiocarbonylamino-diphenylamine 4-Chlor-4'-(N-methyl- Biperazinyl )-thiocaronylamino-diphenylamine ll 91 l Tests on rats infected with Fasciola hepatica White laboratory rats were artificially infected with liver leeches (Fasciola hepatica). After expiry of the preparation time the attack of the rats by liver leech 55 was determined by three independent droppings analyses.

For the test, groups of four attacked rats were treated with the active substance in the form of a suspension 5 good 4 good 5 good 5 good 5 good 4 good 5 good 5 good 4 good 5 good 5 good 4 good 5 good 5 good 3 good 3 good 5 good applied via a stomach probe on 3 subsequent days, once daily. In;the35 week after administration of the active substance a weekly droppings analysis. was carried out on the content of liver leech eggs. At the end of 5 weeks from the start of the test, the test animals were killed and the presence of any liver leeches was determined. Results are shown in the following table. A

droppings control Daily No. of General of egg excretion I I Active Substance dose times liver Condition in mg/kg before after leeches body weight medicamedicaafter tion tion section N-[4-(4'-Nitro phenoxy)- I phenyl]-N'N'- imethyl- 200 ppsinega- 0-0-0-0 good thio urea tlve tive Active Substance -continued Daily dose in mg/kg body weight before medication after medication No. of

liver leeches after section General Condition phenyl]-N'N'-diethylthio urea N[4-(4'-Nitrophenoxy)- phenyl]-N'N'-dipropylthiourea N-[4-(4'-Chlorphenoxy)- phenyl]-N'N'-diethylthio urea N-[4-(4'-Nitrophenoxy)- phenyl]-N'N' dibutylthio urea N-[4(4'-Nitrophenoxy)- 2chlorphenyl]-N'N'-dicthylthio urea N-[4-(4'-Nitrophenoxy)- 3-chlorphenyl]-NN-diethylthio urea N-[4-(4'-Chlorphenoxy)- 3-caboxyphenyl]-N'N'- diethylthio urea N-[4-(4'-Nitrophenoxy)- phenyl]-N'N'-pentamethylenthio urea N-[4-(4'-Nitrophenoxy)- phenyl]-N'N'-dihexylthio urea N-[4-(4'-Nitrophenoxy)- phenyl]N'-methyl-N-propylthio urea N-[4-(4'-Aminophenoxy)- phenyl]-N'N'-diethylthio urea N-[4-(4-Nitrophenoxy)- phenyl]-N'-methyl-N'- ethylthio urea N-[4-(4'-Bromphenoxy)-phenoxy)-pl1enyl]-N'N'-dihexylthio urea N-[4-(4'-Nitrophenylthio)- phenyl]-N'N'-diethylthio urea N-[4-(4-Methylanilino)- phenyl]-N'N'-diethylthio urea N-[4-(4'-Chlorphenylthio)- phenyl]-N'N'-diethylthio urea N-[4-(4-Chlorphenylthio)-3- carboxyphenyl] -N N -dimethylthio urea N[4-(4-N.N-Dimethylaminoanilino)-phenyl]- NN-dibutylth|o urea N-[4-(4'-Nitrophenoxy)- phenyl]-N'-ethyl-N'-sec. butylthio urea N-[4-(4'-Methylphenoxy)- phenyl]-N'N'-diethylthio urea 4-Methoxy-4-(N-methylpiperazinyl)-thiocarbonylamino-diphenylether 4-Methylthi0-4'-(N-methylpiperazinyl)-thiocarbonylamino-diphenylamine 4-Etl1yl-4'-(N-methylpiperazinyD-thiocarbonylamino-di henylamine, 4-Chlor-f-(N-n'1ethylpiperazinyl )-thiocarbonylamino-diphenylamine Tests on mice infected with H'ymenolepis nana The active substance was administered to white mice in the form of a suspension by means of a stomach Hymenolepistnana. Five animals'were used per test. Each group of animals had the active substance administered once daily for 3 subsequent days. The animals were killed 8 days after the beginning of treatment and good good

good

good

good

good

good

good

good

good

good

good

good

good

good

good good good

good

good

good

good.

good

sectioned.

Evaluation after section of the test animals took place by counting the number of ringworms found in probe, the white mice being artificially infected with 65 the gut. As control,untreated but similarly and simultaneously infected mice were used. The agent was received by the mice without any symptoms. Results are shown in the following table.

Active Agents Daily dose Attack of Action on mg/kg 5 test control body weight animals on animals on section section N-[4-(4'-Chlorphenoxy)-phenyl1- i N'N'-diethylthio urea 750 Q-O-O-O-O 3-4-15-18-19 N-[4-(4'-Nitrobenoxy)-phenyl]- N N'-dibutylthio urea 750 0-0-0-0-0 1-8-11-20-39 N-l4-(4'-Methylphenylthio)- phenyl]-N'N'-diethylthio urea 750 0-00-3-4 l-2-3-45 N-[4-(4'-Chlorphenylthio)- phenyl]-N'N'-diethy1thio urea. 750 00-0-0-0 2-2-7-8-8 N-[4-(4-Chloranilino)-phenyl]- N'N'-diethylthio urea v750 0-0-0-0-1 0-1-2-2-4 N-[4-Anilinophenyl]-N'N'-diethylthio urea 750 0-0-0-4-5 1-2-3-4-5 4-Nitro 4'-( N-methylpiperazinyl-amino-diphenylether 750 0-0-0-1-1 0-4-13-13-23 4-Methylthio-4'-(N-methylpiperazinyl )-thiocarbonyl- 750 0-0-0-0-0 l 1-13-16-23-32 amino-diphenylamine 4-Chlor-4'-(N-methylpiperazinyl)-thiocarbonylamino- 750 4-0-0-2-5 0-6-7-8-9 diphenylamine Tests on mice infected with Enterobius took place after section of-the test animals by counting The active substance was administered in the form of the number of mouse Enterobius in the gut. Similarly a suspension to white mice via a stomach probe, the 25 infected by untreated mice served -as control.

mice having previously been infected with mouse En- The agent was affected by the'rnice without sympterobius. Five animals were used per test. Each group toms. Results are expressed in the following table.

of animals had the active substance administered for 3 In this table subsequent days, once daily. l

The daily dose per animal was 750 mg active sub- 30 stance per kg of body weight. l= adult form On the 6th day after the beginning of the treatment,

the animalswere killed and sectioned. The-evaluation animal dead I v 1=juveni1e form.

Daily dosage Attack of Attack of control nyl]-N'N'-diethylthio urea 750 0-0-0- 8/Ll-8/Ll-l4/Ll- O-O l5/L1-20/L1 N-[4-(4'-Nitrophenoxy)- 750 0-0-0- 10/1 -l2l1 -13/L1- urea N-[4-(4-Methoxyphenoxy)- 750 0-0-0- 3-5/Ll-6/L1-7/ phenyll-N'N '-dimethylthio 1-2/1 1-8/Ll urea N-[4-(4'-Nitrophenoxy)- 750 0-0-0- 4/Ll-13/Ll-l5/L- phenyl]-NN'-ethylenthio 2-2 l8/Ll-20/Ll urea N-[4-(4'-Methoxyphenoxy)- 750 0-0-1-2/ +-2-3/L-4/Llphenyl]-N'N'-dibutylthio L-3 l2/Ll urea urea

N-[4-(4'-Chloranilino)- 750 0-0-0- l0/Ll-12/Ll-16/ phenyl]-N'N'-diethylthio 0-0 Ll-20/Ll-24/Ll urea urea

N-[4-(4'-Methylanilino)- 750 0-0-0- l0/l-l2/l-l3/Llurea 4-Methoxy-4'-(N-methyl 750 0-0-0- 3/1/1-3/2/3-7/ piperazinyl)-thiocarbonyl- 0/2/2- 3/L-8/8/4-19/4/B amino-diphenylether 0/2/3 4-Nitro-4'-(N-methylpipera- 750 0-0-1-1/ 5/9/8-6/5/5-9/ zinyll )-thiocarbonylaminolL-3 9/10-13/2/2-20/ dip enylether 4-Methylthio-4'-(N-methyl- 750 0-0-0- 5/4/4-6/3/3-10/ piperazinyl )-thiocarbonyl- 0-0 5/4-12/12/10-17/ amino-diphenylamine 9/7 4-ethyl-4 -(N-methylpipera- 7S0 l/3L-0- 3/1/1-3/2/3-7/ zinyl)-thiocarbony1arnino- 0-0-0/1 3L-8/8/4-19'l4/B diphenylamine 4-Chlor-4'-(N-methylpipera- 750 1-0-0- 3/1 1 -3/2/3-7/3L- zinyl)-thiocarbonylamino- 0-0 8/8/4-19/4/8 diphenylamine In the following use forms of the new thio ureas of general formula I are described. Parts given are parts by weight. Pasty active substance concentrates Such semi-solid or oily active substance concentrates have, for example, the following composition:

a. 40 parts N-[4-(4'-nitrophenoxy)-phenyl]-NN'- dibutylthio urea parts Bolus alba 2 parts sodium lignosulphonate 0.2 parts Sodium benzoate 1.0 parts carboxymethyl cellulose 46.8 parts water b. 30 parts N-[4-(4'-chloro-3'-methylphenoxy)-phenyl] N'N'-diethylthio urea 70 parts peanut oil The active substances were milled together to the finest possible particle size (5-10 microns) together with carriers, distribution agents and other additives. The resulting homogeneous concentrateswere administered to domestic and useful animals by means of .a drenching pistol. These concentrates were used for the temporary deworming of a number of farm animals, for example, for deworming a flock of sheep attacked by Haemonchus spp., Trichostrongylus spp. etc. Powder concentrate i For the manufacture of an (a) 50% and (b) 25% powder concentrate the following materials were used:

a. 50' parts N-[4-(4 nitrophenoxy)-phenyl]-NN- diethylthio urea 3 parts polyoxyethylene sorbitan monooleate 3 parts ligninsulphonic acid sodium salt 44 parts Bolus alba b. 25 parts N-[4-(4'-chlorophenoxy)-phenyl]-NN;

diethylthio urea 3 parts polyvinylpyrrolidone 3 parts dodecylbenzene sulphonate 39 parts Kieselguhr 20 30 parts Bolus alba The active substances given were, for example, coated onto the carrier material as an acetonic solution. Thereafter dispersing agents and wetting agents were added thereto and the concentrate milled to homogeneity. Such powder concentrates can be mixed with fodder, added to conventional fodder premixes or can be diluted with water to potable drinks. In addition, these powder concentrates can be directly enclosed in gelatine capsules, and, for example, administered to dogs or worked into food in the form of tabletted food pellets.

What we claim is:

1. A compound of the formula in which R, ishydrogen, halogen, nitro, low alkyl, low alkoxy or low alkylthio, each of the latter having alkyl groups with 1 to 4 carbon atoms; R is hydrogen, halogen, nitro, low alkyl or low alkoxy; R is hydrogen; each of R and R is alkyl offrom l to 4 carbon atoms; and X is imino. v

2. A compound according to claim 1 in-which R is halogen, nitro or low alkyl; R, and R are hydrogen; each of R and R is alkyl of from 1 to 4 carbon atoms; and X is imino. 4

3 N-[4-(4'-chloroanilino)-phenyl]-N',N'-diethylthiourea according to claim 2.

4. N- [4-(4-methylanilino)-phenyl]-N ,N -diethylthiourea according to claim 2. 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 in which R1 is halogen, nitro or low alkyl; R2 and R3 are hydrogen; each of R4 and R5 is alkyl of from 1 to 4 carbon atoms; and X is imino.
 3. N-(4-(4''-chloroanilino)-phenyl)-N'',N''-diethylthiourea according to claim
 2. 4. N-(4-(4''-methylanilino)-phenyl)-N'',N''-diethylthiourea according to claim
 2. 